Orphan GPR110 targeted by N-docosahexaenoylethanolamine: an omega-3 fatty acid-dependent mechanism for brain development

Authors

• JW Lee
• G Kharebava
• BX Huang
• MA Rashid
• S Patnaik
• J Marugan
• HY Kim

Abstract

Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 fatty acid essential for proper brain development and cognitive function. N-docosahexaenoylethanolamine (synaptamide), an endogenous metabolite of DHA, potently promotes neuritogenesis, synaptogensis and neurogenesis, however, the underlying molecular mechanism has not been determined. Here, we demonstrate that orphan G-protein coupled receptor 110 (GPR110) is the synaptamide receptor, mediating synaptamide-induced neurogenesis and neurite outgrowth in a cAMP-dependent manner. Mass spectrometry-based proteomic characterization and cellular fluorescence imaging probed by chemical analogues of synaptamide revealed specific binding of GPR110 to synaptamide. Disruption of this binding abolished but GPR110 overexpression enhanced synaptamide-induced bioactivity. GPR110 was highly expressed in fetal brains while their exposure to synaptamide significantly increased neurogenesis, indicating in vivo relevance of synaptamide/GPR110 signaling for neurodevelopment. GPR110 deorphanized as a functional synaptamide receptor provides a novel target for neurodevelopmental control and offers new insight into the mechanism by which omega-3 fatty acids promote brain development and function.

Scientific Focus Area: Neuroscience

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